Muscle wasting remains a cause of morbidity and mortality in patients that chronically abuse alcohol. The etiology of this myopathy is multifactorial but largely the result of a decreased rate of protein synthesis. Data from our studies completed during the past funding period reveal that alcohol impairs translational control of protein synthesis by modulating key steps in peptide-chain initiation. This alcohol-induced defect is manifested not only under basal conditions but also as a diminished responsiveness to various nutrient signals, such as leucine and insulin-like growth factor (IGF)-I. Our data suggest that these alcohol-induced defects are in part mediated by alterations in the mTOR-nutrient signaling complex (NSC) in skeletal muscle. The long-term goal of this work is to elucidate the cellular and molecular mechanisms by which ethanol regulate nutritional signals leading to the development of skeletal muscle myopathy. To address the questions implicit in this goal, the proposed research has the following specific aims: (1) Delineate the mechanism by which alcohol modulates mTOR-dependent signaling in muscle by characterizing alcohol- induced alterations in the amount or binding of mTOR regulatory factors (e.g., raptor, rictor, G/?L) as well as the role of TSC1/2, Rheb and REDD1;(2) Elucidate the mechanism by which alcohol impairs the normal anabolic response to nutritional signals in muscle, specifically the response to leucine;(3) Identify mechanisms by which alcohol decreases IGF-I availability and produces IGF-I resistance in muscle thereby regulating the mTOR-NSC;and (4) Examine the molecular basis for the observed gender-sensitive changes in muscle protein synthesis as they related to the leucine unresponsiveness seen in females provided alcohol. Collectively, these studies are unique in this field because they integrate in vitro and in vivo approaches that permit both detailed molecular mechanisms as well as the physiological relevance of the observations to be identified. These studies will enhance understanding of this critical regulatory system and the integrative control mechanisms exerted by key hormone and nutrient signals leading to a more thorough understanding of alcohol myopathy. The proposed studies have a translational underpinning in that the data may lead to development of novel clinical interventions designed to reverse alcoholic myopathy during rehabilitation.